B-Cell Depletion Promotes Aortic Infiltration of Immunosuppressive Cells and Is Protective of Experimental Aortic Aneurysm

Abstract

Objective B cell depletion therapy is widely used for treatment of cancers and autoimmune diseases. B cells are abundant in abdominal aortic aneurysms (AAA), however, it is unknown whether B cell depletion therapy affects AAA growth. Using experimental models of murine AAA, we aim to examine the effect of B cell depletion on AAA formation. Approach and Results Wild-type or Apolipoprotein E knockout mice were treated with mouse monoclonal anti-CD20 or control antibodies and subjected to an elastase perfusion or angiotensin II-infusion model to induce AAA, respectively. Anti-CD20 antibody treatment significantly depleted B1 and B2 cells, and strikingly suppressed AAA growth in both models. B cell depletion resulted in lower circulating IgM levels, but did not affect the levels of IgG or cytokine/chemokine levels. Although the total number of leukocyte remained unchanged in elastase perfused aortas following anti-CD20 antibody treatment, the number of B cell subtypes was significantly lower. Interestingly, plasmacytoid dendritic cells (pDCs) expressing the immunomodulatory enzyme indole 2,3-dioxygenase (IDO) were detected in the aortas of B cell depleted mice. In accordance with an increase in IDO+ pDCs, the number of regulatory T cells was higher while the expression of pro-inflammatory genes was lower in aortas of B cell depleted mice. In a coculture model, presence of B cells significantly lowered the number of IDO+ pDCs without affecting total pDC number. Conclusions The present results demonstrate that B cell depletion protects mice from experimental AAA formation and promotes emergence of an immunosuppressive environment in aorta.

Involvement of B Cells, Immunoglobulins, and Syk in the Pathogenesis of Abdominal Aortic Aneurysm

“…In Apoe ‐deficient or Ldlr ‐deficient hyperlipidemic mice, AAA can be induced with a continuous infusion of angiotensin II. Our finding that B cells were required for the full development of AAA after CaCl 2 challenge was consistent with previous reports that showed that muMT mice were protected from elastase‐induced AAA and that B cell depletion by anti‐CD20 antibody abrogated AAA development induced by angiotensin II in Apoe ‐deficient mice . On the other hand, a state of total lymphocyte deficiency attenuated atherosclerosis in Apoe ‐deficient mice but not angiotensin II–induced AAA; furthermore, muMT mice were not protected from elastase‐induced AAA .…”

“…On the other hand, a state of total lymphocyte deficiency attenuated atherosclerosis in Apoe ‐deficient mice but not angiotensin II–induced AAA; furthermore, muMT mice were not protected from elastase‐induced AAA . A potential explanation for these controversial results could be that T cells participated in AAA pathogenesis by modulating the effect of B cells . For example, the deletion of all T cells has been reported to abrogate the effect of regulatory T cells in suppressing AAA formation in an angiotensin II–induced model .…”

“…Indeed, a series of studies have demonstrated that B cells promoted AAA by producing immunoglobulins against fibrinogen, which then activated the complement pathway, in an elastase‐induced mouse model . Consistently, it has been reported that the depletion of B cells with an anti‐CD20 antibody protected the aorta from AAA development in the elastase‐induced model and in an angiotensin II–induced model in Apoe ‐deficient mice . However, the involvement of B cells in AAA pathogenesis is controversial.…”

“…13,14 Consistently, it has been reported that the depletion of B cells with an anti-CD20 antibody protected the aorta from AAA development in the elastase-induced model and in an angiotensin II-induced model in Apoe-deficient mice. 15 However, the involvement of B cells in AAA pathogenesis is controversial. Another study reported that, with the same elastase-induced AAA model, B cell-deficient mice developed AAA equivalent to wild-type (WT) mice, and B2-cell administration ameliorated AAA development.…”

Aortic Aneurysms

“…37 Consistent with this finding, Ailawadi’s group reported that depletion of B cells by anti-CD20 antibody reduced AAA in both AngII-induced and elastase-induced AAA models. 42 …”